SAR profiles of spirocyclic nicotinamide derived selective HDAC1/HDAC2 inhibitors (SHI-1:2).
A potent family of spirocyclic nicotinyl aminobenzamide selective HDAC1/HDAC2 inhibitors (SHI-1:2) is profiled. The incorporation of a biaryl zinc-binding motif into a nicotinyl scaffold resulted in enhanced potency and selectivity versus HDAC3, but also imparted hERG activity. It was discovered that increasing polar surface area about the spirocycle attenuates this liability. Compound 12 induced a 4-fold increase in acetylated histone H2B in an HCT-116 xenograft model study with acute exposure, and inhibited tumor growth in a 21-day efficacy study with qd dosing.
Methot
Joey L
JL
Department of Drug Design and Optimization, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA. joey_methot@merck.com
Hamblett
Christopher L
CL
Mampreian
Dawn M
DM
Jung
Joon
J
Harsch
Andreas
A
Szewczak
Alexander A
AA
Dahlberg
William K
WK
Middleton
Richard E
RE
Hughes
Bethany
B
Fleming
Judith C
JC
Wang
Hongmei
H
Kral
Astrid M
AM
Ozerova
Nicole
N
Cruz
Jonathan C
JC
Haines
Brian
B
Chenard
Melissa
M
Kenific
Candia M
CM
Secrist
J Paul
JP
Miller
Thomas A
TA
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020650:Combinatorial Chemistry Techniques; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D045325:HCT116 Cells; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006657:Histones / Q000032:analysis; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D009536:Niacinamide / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020033:Protein Isoforms; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays; D000099186:Histone Deacetylase 3
D000970:Antineoplastic Agents; D001549:Benzamides; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006657:Histones; D009536:Niacinamide; D020033:Protein Isoforms; D013141:Spiro Compounds; D000099186:Histone Deacetylase 3; C000606913:KCNH2 protein, human